Numerous gastro-intestinal peptide hormones are involved in the regulation of food intake and energy homeostasis (e.g. CCK, GLP-1, PYY, ghrelin). Recently, also Oxyntomodulin (Oxm), a product from the proglucagon gene in intestinal L-cells was shown to have anorexigenic properties in both rodents and humans. A four week long clinical study in obese humans demonstrated that repeated subcutaneous administration of Oxm reduced food intake and caused a significant body weight loss. Since a specific Oxm receptor remains to be found, it has been suggested that many of the physiological effects are mediated through GLP-1 and glucagon receptor activation. Indeed, Oxm binds and activates both GLP-1 and glucagon receptors albeit with lower affinity and potency than the cognate ligands. Several recent papers have demonstrated the power of simultaneous GLP-1/glucagon receptor targeting by constructing dual agonists and comparing the weight lowering effect in DIO mice and knock-out mouse models. Treatment with a balanced GLP-1/glucagon receptor co-agonist resulted in robust reduction in body weight and fat mass, exceeding that of a pure GLP-1 receptor agonist, and with glucose control comparable to that of a GLP-1 receptor agonist. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon treatment with a GLP-1/glucagon receptor co-agonist than with a pure GLP-1 receptor agonist. In addition, GLP-1/glucagon receptor co-agonist-treatment increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. In GLP-1- or glucagon receptor knock-out mice GLP-1/glucagon receptor co-agonists demonstrated a reduced, but still significant effect on body weight loss compared to wild-type animals thus supporting the hypothesis that simultaneous activation of the GLP-1 and glucagon receptors results in superior weight loss.
One physiological effect of glucagon receptor activation is to increase blood glucose levels by stimulating hepatic glycogenolysis and gluconeogenesis. Glucagon receptor activation has additionally been shown to increase energy expenditure and decrease food intake in both rodents and humans.
In a recent study 16 human volunteers were infused with glucagon, GLP-1, a combination of glucagon and GLP-1, or saline. The energy intake during the meal was significantly reduced (13%) in the combination group, but not affected when either hormone was given alone.
In another study, energy expenditure (EE) was measured after infusions of GLP-1, glucagon or the combination hereof into healthy human volunteers. The study showed that glucagon and the combination of glucagon and GLP-1 increased EE to a similar degree, while GLP-1 was without effect. Glucagon infusion was accompanied by a rise in plasma glucose levels, but co-infusion of GLP-1 in addition to glucagon rapidly reduced this excursion. The importance of GLP-1 receptor activity in preventing glucagon receptor-mediated hyperglycaemia in obese mice was further demonstrated using a family of GLP-1/glucagon receptor co-agonist peptides varying in murine receptor potency for the two receptors. The study indicated that a balanced GLP-1/glucagon receptor co-agonist peptide exhibited the optimal therapeutic profile for weight loss while mitigating the hyperglycaemic risk associated with glucagon receptor activation.
All together, these studies support the concept of a dual GLP-1 and glucagon agonism as a potential target for treatment of obesity.
The vast majority of GLP-1/glucagon receptor co-agonists have been obtained using glucagon or oxyntomodulin as starting point and GLP-1 activity has been improved by various amino acid mutations. Glucagon has a poor physical and chemical stability, and this is also observed for many glucagon based co-agonists.
Accordingly, a need remains for GLP-1/glucagon receptor co-agonists with improved stability, including improved chemical and physical stability.